EFFECTS OF GESTATIONAL AND OVERT DIABETES ON HUMAN PLACENTAL CYTOCHROMES P450 AND GLUTATHIONE-S-TRANSFERASE

The placenta possesses the ability to metabolize a number of xenobioti cs and endogenous compounds by processes similar to those seen in the liver, Animal and in vivo studies have observed that the presence of d iabetes alters the expression of hepatic metabolizing enzymes (cytochr ome P450 and glutathione S-transferase); however, it is unknown whethe r similar alterations occur in the human placenta, To evaluate whether diabetes has any effect of placental xenobiotic metabolizing activity , the catalytic activities of 7-ethoxyresorufin O-deethylation (EROD, CYP1A1), chlorzoxazone 6-hydroxylation (CYP2E1), dextromethorphan N-de methylation (CYP3A4), dextromethorphan O-demethylation (CYP2D6), and l -chloro-2,4-dinitrobenzene (CDNB) conjugation with glutathione (glutat hione S-transferase, GST) from placentas of diet (class A,) and insuli n-dependent (class A(2)) gestational diabetics and overt diabetics wer e compared with matched controls. EROD activity (CYP1A1) ranged from 0 .29 to 2.67 pmol/min/mg protein. However, no differences were observed among overt or gestational diabetics and their respective matched con trols. CDNB conjugation (GST) ranged from 0.275 to 1,65 units/min/mg p rotein, In contrast to that observed with CYP1A1, a small but statisti cally significant reduction in GST activity was noted in overt diabeti cs as compared with their matched controls and gestational diabetics. CYP2E1, 2D6, and 3A4 enzymatic activities were not detected in human p lacental tissue. GST protein was detectable in all tissues studied, bu t no CYP protein could be detected in any of the tissues, Thus, it see ms that pregnant women with overt diabetes have reduced GST activity i n the placenta, which could potentially result in the exposure of the fetus to harmful electrophiles. However, the full clinical significanc e of this finding remains to be elucidated.